Malaria, caused by Plasmodia sporozoites (spz) is a leading contributor to morbidity and mortality in many parts of the world. Protection by natural infection allows intermittent episodes of parasitemia to occur and decays rapidly once exposure ceases. By contrast, immunization of humans and laboratory rodents with irradiated (gamma) spz results in a sterile and long-lasting protection. Because gamma-spz undergo partial schizogony, the liver becomes a major depot of plasmodial antigens required for induction and maintenance of protective immunity. The mechanisms of protection include Ig, CD4+T cells, and particularly effector CD8+ T cells that target infected hepatocytes and release INF-gamma to eliminate the parasite. The mechanisms of sustained protection and the role of the liver as an immune organ in promoting long-term immunity, however, remain unknown. Therefore, the overall objective of this proposal is to determine whether memory CD8+ T cells mediate long-lasting protection and to understand the involvement of the liver in this process. CD8+ T cells that constantly ingress to the liver to become the sentinel short-lived effector T cells could maintain protection. Instead, based on our observations that memory CD8+ CD44hiCD45RBlo T cells are present in livers of long- term immune mice, our hypothesis is that liver memory CD8+ T cells play a role in protection. To test this hypothesis, experiments are propose to examine whether (1) CD8+ T cells from long- and short-term protected mice can be distinguished by activation/memory markers, functional properties, and apoptosis; (2) memory CD8+ T cells are present in mice that do not develop long-term protection; (3) APC, cytokines, CD4+ T and NK T cells are required for the maintenance of memory CD8+T cells. Results from models of protective immunity induced by gamma-spz have formed the basis for the current strategy to develop anti-malaria vaccines, the improvement of which awaits the understanding of cellular memory responses that underlie long-lasting protective immunity.